This FIRCA collaboration originated in the laboratory of Prof. H.M. Temin at McArdle Laboratory for Cancer Research, University of Wisconsin-Madison. The initial collaboration was supported by a FIRCA award to Dr. Temin and Dr. Altaner in 1992, and after Dr. Temin's decease, the present collaboration spontaneously evolved based on new experiments with Dr. Kathleen Boris-Lawrie -that time post-doctoral fellow in Dr. Temin's laboratory. This FIRCA collaboration is a mutually beneficial and complementary combination of Dr. Boris-Lawrie's innovative retrovirus vector development with Dr. Altaner's animal model system. Bovine leukemia virus (BLV) is a genetically complex retrovirus and the etiologic agent of enzootic persistent lymphocytosis and lymphosarcoma in cattle. BLV is genetically related to human T-cell leukemia virus (HTLV) and to human immunodeficiency virus (HIV), and the rapid and definitive course of BLV disease in rabbits provides an experimentally tractable model to study pathogenesis of complex retroviruses. BLV encodes the three common retroviral structural/enzymatic proteins (Gag, Pol, Env) and characteristic complex regulatory proteins (Tax, Rex) and accessory proteins (RIII, GIV) that are necessary for pathogenesis. We have established for the first-time unique retrovirus vectors that replicate the BLV structural/enzymatic genes independently of these regulatory and accessory proteins. These structural gene vectors (SGV) have been proposed as a prototype safe and preventative vaccine against pathogenic infection caused by complex retroviruses. Our previous experiments validated the hypothesis that the BLV SGVs are infectious, immunogenic, and lack pathogenicity. The results demonstrated that BLV SGV infect the natural BLV target cell population, induce anti-BLV antibodies, and unlike BLV, lack pathogenicity in rabbits. The next step is to test the hypothesis that infection with BLV SGV induces BLV-specific cell- mediated immunity and protects against pathogenic BLV infection. This experiments proposed in this FIRCA application will comprise a critical step in the evaluation of the novel BLV SGV preventative vaccination approach and provide important insight into the role of BLV regulatory and accessory genes in BLV immune response and pathogenesis. Future plans include extension of knowledge from the BLV system to evaluate related SGV based on HTLV and HIV that are postulated to be safe, preventative vaccines against these pathogenic human retroviral disease.